Revisiting Heart Failure

In a satellite symposium organized by LRI-Therapharma during the recent annual convention of the Philippine Heart Association, Dr. Emil Canonigo, senior consultant at Cardinal Santos Memorial Hospital; and Dr. Maria Katrina Cruz Tan, head of the Cardio-Oncology section of St. Luke’s Medical Center, updated the audience— mostly heart specialists from all over the country—on how patients with heart failure, either due to anti-cancer chemotherapy-induced cardiotoxicity or other causes, could benefit from old drugs like candesartan to relieve symptoms and improve long-term outcomes

By Dr. Reuben Ricallo

Managing patients with heart failure (HF) remains one of the major challenges physicians are confronted with in the clinics.

It is now well known that cancer chemotherapy may induce left ventricular dysfunction which may subsequently progress into a dilated or congestive cardiomyopathy. It may also cause potentially life-threatening arrhythmias, even in previously normal hearts of young cancer patients.

Data over the last 15 years also give us a better understanding of different types of HF, which may require different types of management.

‘Middle child’ HF

Dr. Canonigo discussed so-called ‘middle child’ in heart failure— HF with mid-range ejection fraction (HFmrEF) wherein patients have a left ventricular EF (LVEF) in the range of 40-49 percent. The 2016 European Society of Heart Failure (ESC) Guidelines for the Diagnosis and Treatment of Acute and Chronic HF has added HFmrEF to HF with reduced EF (HFrEF) of less than 40 percent; and HF with preserved EF (HFpEF) of 50 percent or higher.

Dr. Canonigo explained that patients with HFmrEF have a milder systolic dysfunction compared to HFrEF, but with some features of diastolic dysfunction. There is an emerging consensus that it is important to identify patients with HFmrEF and stimulate research in this subgroup, which has not been adequately evaluated in clinical trials compared to HFrEF and HFpEF..

Even in the previous 2012 ESC HF guidelines, experts already mentioned that the range of EF between 35 percent and 50 percent represents a ‘grey’ area of HF patients wherein some degree of knowledge gap exists. It was assumed that they represented the HF population with primarily milder systolic dysfunction. Following the 2012 ESC guidelines, more papers in this EF range were published; hence, the latest ESC guidelines acknowledged LVEF between 40 percent and 49 percent as a separate category. HFmrEF was coined, which means either ‘mid-range’ or ‘moderately reduced’ HF.

It is to be recalled that in the overall analysis of CHARM, candesartan treatment was associated with a reduced risk of CV death or hospital admission for chronic HF (HR: 0.84, P<0.0001), while CHARMPreserved did not show a significant effect of candesartan as compared with placebo (HR: 0.89, P=0.118).

Recent CHARM analysis

In the current analysis, researchers aimed to assess time to cardiovascular (CV) death or first HF hospitalisation as a primary outcome across the EF spectrum including HFmrEF. (Lund L, ESC Heart Failure 2017)

“Patients with HFmrEF can benefit from early treatment with anti-HF regimen including candesartan to prevent progression to the more severe HFrEF, which carries a worse prognosis”

Dr. Maria Katrina Cruz Tan, head of the Cardio-Oncology

The findings were as follows:

1. Baseline characteristics in HFmrEF and HFrEF were similar based on age, sex, systolic blood pressure (SBP), ischemic cause and atrial fibrillation (AF) status.
2. There was a similar percentage of patients with diabetes; however, body mass index (BMI) was somewhat higher in HFmrEF than HFrEF.
3. In the analysis, a higher EF was associated with a lower risk of the primary outcome, up to EF of ~40-50 percent, seen by a steep decline of the event rate. Beyond this range, the curve flattens.
4. Similar trends were observed for the secondary outcomes of HF hospitalisation, CV death, all cause hospitalisation, all cause death and recurrent HF hospitalisation.
5. Candesartan reduced CV death and time to first HF hospitalisation in HFrEF (HR: 0.82, P<0.001), HFmrEF (HR: 0.76, P=0.02), but not HFpEF (HR: 0.95, CI: 0.79-1.14).
6. For the treatment effect, analysis showed that candesartan reduced the primary outcome in the HFrEF and HFmrEF range, up to EF ~50 percent.
7. Spline curves for the secondary outcomes were very similar to the primary outcome, with a reduction of events with candesartan up to EF ~35-50 percent. Recurrent HF hospitalisations were reduced irrespective of EF.
8. Spline analyses showed diverging curves of the 95 percent CI at the extremes of the EF spectrum.

According to the study authors, these recent observational data suggest that HFmrEF is similar to HFrEF with respect to most characteristics, but the clinical outcomes are better in HFmrEF, with improvements in outcomes seen with increasing EF, up to 50 percent. A significant treatment effect of candesartan as compared with placebo was seen in HFmrEF and HFrEF, but not HFpEF.

Translating these recent analysis to clinical practice, Dr. Canonigo, said that patients with HFmrEF can benefit from early treatment with anti-HF regimen including candesartan to prevent progression to the more severe HFrEF, which carries a worse prognosis.

PRADA study

Ideally, according to Dr. Tan, cancer patients undergoing treatment, either by chemotherapy or radiation, should be evaluated by a heart specialist and monitored during the cancer treatment for side effects. Dr. Tan presented a clinical trial called the PRADA (Prevention of cardiac dysfunction during adjuvant breast cancer therapy) study, which was a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol in patients undergoing anti-cancer therapy.

The aim of the study was to find out if either or both of these drugs could alleviate the decline in LVEF associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. (Eur Heart J. 2016 Jun 1;37[21]:1671-80)

The authors concluded that in patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Dr. Tan explained that the different types of chemotherapy also have variable effects on the heart. Some anticancer drugs may have a dose-dependent irreversible damage on the heart, while other drugs may cause temporary side effects which resolve with discontinuation of treatment.

Some drugs may also increase the risk of heart attack. So, the cancer specialist should discuss these possible side effects with the patient before initiating treatment.

Potentially cardiotoxic chemotherapeutic agents

Anticancer treatments that may cause cardiac side effects include the following drugs:

1. Anthracyclines (doxorubicin, daunorubicin)
2. Trastuzumab and pertuzumab, which are drugs designed to attack certain cells (the HER2 protein) seen in some breast and other types of cancer
3. Taxanes, which can cause potentially serious arrhythmia. Symptoms include feeling light-headed or syncope, with or without palpitations.
4. Old anticancer drugs like fluorouracil can induce spasms of the coronary arteries that may lead to severe ischemic episodes, even acute myocardial infarction in some cases. However, the adverse effects are reversible with prompt discontinuation of treatment.

Cancer therapy may cause either systolic or diastolic dysfunction, pericarditis which may lead to pericardial fibrosis, and valvular damage causing stenosis or regurgitation.

In cancer patients with pre-existing heart disease, the oncologist or cancer specialist will have to choose an anticancer regimen that is least toxic to the heart, advised Dr. Tan.

Myocardial stunning during chemotherapy

During the open forum of the satellite session, Professor Nanette Wenger from the United States, who was a guest speaker in another session of the annual convention, said that although cancer chemotherapy affects primarily the rapidly dividing cells, normal cells like the heart cells can be “stunned,” similar to what happens during a heart attack, a phenomenon called myocardial stunning. This ventricular stunning may only be temporary, though, based on the US experience.

It would indeed be unfortunate if cancer patients get cured of cancer but subsequently die due to heart failure, said Professor Wenger.

“It would indeed be unfortunate if cancer patients get cured of cancer but subsequently die due to heart failure”